RU2555706C2 - New piperazines as antimalarial drugs - Google Patents

Abstract

FIELD: medicine, pharmaceutics.SUBSTANCE: invention refers to compounds of the structural formula Iwhich can be used for treating and/or preventing malaria caused by Plasmodium falciparum. In formula I: X means CH or N, Rmeans -NO, -N(CH)or -NCH(CHCHOH) and Rmeans hydrogen, methyl, ethyl, n-propyl, isopropyl, tert-butyl, cyanogroup, halogen, methoxygroup, ethoxygroup, n-propoxygroup, isopropoxygroup, trifluoromethyl, difluoromethoxygroup, methylsulphonyl, acetyl or acetylaminogroup; or X means CH, Rmeans hydrogen and Rmeans ethyl, isopropyl, tert-butyl, ethoxygroup, n-propoxygroup, isopropoxygroup, methylsulphonyl, acetylaminogroup or methoxycarbonyl; or X means CH, Rmeans a cyanogroup and Rmeans ethyl, isopropyl, tert-butyl, ethoxygroup, n-propoxygroup, isopropoxygroup, trifluoromethyl, difluoromethoxygroup, trifluoromethoxygroup, methylsulphonyl or acetylaminogroup; or X means CH, Rmeans chlorine and Rmeans ethyl, isopropyl, tert-butyl, ethoxygroup, n-propoxygroup, isopropoxygroup, difluoromethoxygroup, methylsulphonyl or acetylaminogroup; or X means CH, Rmeans a methoxygroup or isopropoxygroup and Rmeans trifluoromethyl; or X means CH, Rmeans methylsulphonyl or ethylsulphonyl and Rmeans trifluoromethyl, ethyl, isopropyl, tert-butyl, ethoxygroup, n-propoxygroup, isopropoxygroup or difluoromethoxygroup.EFFECT: invention refers to a pharmaceutical composition containing the above compounds, and to using the compounds for preparing the pharmaceutical composition.22 cl, 2 tbl, 73 ex

Description

The present invention relates to new compounds of formula I. The present invention also relates to related matters, including methods for producing compounds, pharmaceutical compositions containing one or more compounds of formula I, and, in particular, their use as drugs for the treatment or preventing malaria infections or for treating or preventing other protozoal diseases such as sleeping sickness, Chagas disease, amoebiasis, giardiasis, trichomoniasis, toxoplasmosis and leishmaniasis.

State of the art

Numerous severe diseases affecting people, as well as pets and livestock, are caused by protozoan microorganisms such as, for example, Kinetoplastida, Apicomplexa, Anaerobic Protozoa, Microsporidia and Plasmodium. Of these diseases, malaria is the most clinically significant.

Malaria is one of the most severe and complex diseases affecting humanity in the 21st century. This disease affects approximately 300 million people worldwide and from 1 to 1.5 million people per year die from it. Malaria is an infectious disease caused by four types of Plasmodium protozoan parasites, of these four P. Falciparum is the most dangerous. All attempts to develop vaccines against P. Falciparum have been unsuccessful. Therefore, the therapeutic and prophylactic means of combating malaria are limited to drugs. There are several classes of antimalarial drugs. The most widely used are quinoline antimalarials, for example, chlorchine, which is a particularly effective drug used both for prevention and treatment. However, resistance to many of the current antimalarial medicines is rapidly developing, which threatens people in areas of the malaria epidemic. Reports of multi-drug resistant strains of malaria parasites make the search for new anti-malarial drugs particularly necessary.

P. Falciparum enters the human body through the bites of an Anopheles female mosquito (it can also be transmitted by blood transfusion from asymptomatic donors; almost all infected blood components, including red blood cells, platelet mass, white blood cells, cryoprecipitate and fresh plasma, can transmit malaria). The parasite Plasmodium initially multiplies in the liver and, in subsequent stages of the infection cycle, multiplies in red blood cells. At this stage, the parasite destroys hemoglobin and uses the products of destruction as nutrients for growth.

Limitations of the existing arsenal of antiprotozoal chemotherapeutic agents emphasize the need for new drugs in this area of therapy. The present invention relates to the development of new low molecular weight, non-peptide, non-quinoline compounds of the formula I, which are useful for the treatment and / or prevention of protozoal infections, preferably for the treatment and / or prevention of malaria, in particular malaria caused by Plasmodium falciparum.

Piperazine derivatives as antimalarials are also disclosed in WO 2007/046075. The compound proposed in WO 2007/046075, which is most similar to some of the compounds claimed in the present invention, is the compound of example 54, which in the present invention corresponds to the comparative compound of example 1. However, the compounds claimed in the present invention, which are most similar in structure with the compound of example 54, proposed in WO 2007/046075, have in vitro activity in relation to the strain P. Falciparum NF54, located in the erythrocyte stages, in the presence of 50% serum, significantly higher than the activity of the compound of example 54 proposed in WO 2007/046075 (see table 1 below).

Detailed description of the invention:

i) The present invention relates to new compounds of formula I:

wherein

- X is CH or N;

R ¹ is —NO ₂ , —N (CH ₃ ) ₂ or —NCH ₃ (CH ₂ CH ₂ OH); and

R ² is hydrogen, methyl, ethyl, n-propyl, isopropyl, tert-butyl, cyano, halogen, methoxy, ethoxy, n-propoxy, isopropoxy, trifluoromethyl, difluoromethoxy, methylsulfonyl, acetyl or acetylamino; or

- X is CH, R ¹ is hydrogen and R ² is ethyl, isopropyl, tert-butyl, ethoxy, n-propoxy, isopropoxy, methylsulfonyl, acetylamino or methoxycarbonyl; or

- X is CH, R ¹ is cyano and R ² is ethyl, isopropyl, tert-butyl, ethoxy, n-propoxy, isopropoxy, trifluoromethyl, difluoromethoxy, trifluoromethoxy, methylsulfonyl or acetylamino; or

- X is CH, R ¹ is chloro and R ² is ethyl, isopropyl, tert-butyl, ethoxy, n-propoxy, isopropoxy, difluoromethoxy, methylsulfonyl or acetylamino; or

- X is CH, R ¹ is methoxy or isopropoxy, and R ² is trifluoromethyl; or

- X is CH, R ¹ is methylsulfonyl or ethylsulfonyl and R ² is trifluoromethyl, ethyl, isopropyl, tert-butyl, ethoxy, n-propoxy, isopropoxy or difluoromethoxy, preferably trifluoromethyl, tert-butyl, n-propoxy or isopropyl.

ii) In another embodiment, the present invention relates to compounds of formula I according to Embodiment i), wherein

- X is CH or N;

R ¹ is —NO ₂ , —N (CH ₃ ) ₂ or —NCH ₃ (CH ₂ CH ₂ OH); and

R ² is hydrogen, methyl, ethyl, n-propyl, isopropyl, tert-butyl, cyano, halogen, methoxy, ethoxy, n-propoxy, isopropoxy, trifluoromethyl, difluoromethoxy, methylsulfonyl, acetyl or acetylamino; or

- X is CH, R ¹ is hydrogen and R ² is ethyl, isopropyl, tert-butyl, ethoxy, n-propoxy, isopropoxy, methylsulfonyl, acetylamino or methoxycarbonyl; or

- X is CH, R ¹ is cyano and R ² is ethyl, isopropyl, tert-butyl, ethoxy, n-propoxy, isopropoxy, trifluoromethyl, difluoromethoxy, trifluoromethoxy, methylsulfonyl or acetylamino; or

- X is CH, R ¹ is chloro and R ² is ethyl, isopropyl, tert-butyl, ethoxy, n-propoxy, isopropoxy, difluoromethoxy, methylsulfonyl or acetylamino; or

- X is CH, R ¹ is methoxy or isopropoxy, and R ² is trifluoromethyl.

iii) In another embodiment, the present invention relates to compounds of formula I according to Embodiment i), wherein

X is CH or N;

R ¹ is —NO ₂ , —N (CH ₃ ) ₂ or —NCH ₃ (CH ₂ CH ₂ OH); and

R ² is ethyl, isopropyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, trifluoromethyl, difluoromethoxy, methylsulfonyl or acetylamino; or

- X is CH, R ¹ is hydrogen and R ² is ethyl, isopropyl, tert-butyl, ethoxy, n-propoxy, isopropoxy, methylsulfonyl, acetylamino or methoxycarbonyl; or

- X is CH, R ¹ is cyano and R ² is ethyl, isopropyl, tert-butyl, ethoxy, n-propoxy, isopropoxy, trifluoromethyl, difluoromethoxy, trifluoromethoxy, methylsulfonyl or acetylamino; or

- X is CH, R ¹ is chloro and R ² is ethyl, isopropyl, tert-butyl, ethoxy, n-propoxy, isopropoxy, difluoromethoxy, methylsulfonyl or acetylamino; or

- X is CH, R ¹ is methoxy or isopropoxy, and R ² is trifluoromethyl.

iv) In another embodiment, the present invention relates to compounds of formula I according to Embodiment i), wherein

R ¹ is —NO ₂ , —N (CH ₃ ) ₂ or —NCH ₃ (CH ₂ CH ₂ OH); and

R ² is hydrogen, methyl, ethyl, n-propyl, isopropyl, tert-butyl, cyano, halogen, methoxy, ethoxy, n-propoxy, isopropoxy, trifluoromethyl, difluoromethoxy, methylsulfonyl, acetyl or acetylamino.

v) In another embodiment, the present invention relates to compounds of formula I according to Embodiment i), wherein

R ¹ is —NO ₂ , —N (CH ₃ ) ₂ or —NCH ₃ (CH ₂ CH ₂ OH); and

R ² is ethyl, isopropyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, trifluoromethyl, difluoromethoxy, methylsulfonyl or acetylamino.

vi) In another embodiment, the present invention relates to compounds of formula I according to Embodiment iv) or v) wherein X is CH.

vii) In another embodiment, the present invention relates to compounds of formula I according to Embodiment iv) or v), wherein X is N.

viii) In another embodiment, the present invention relates to compounds of formula I corresponding to any of embodiments iv) to viii), wherein R ¹ is —NO ₂ .

ix) In another embodiment, the present invention relates to compounds of formula I corresponding to any of embodiments iv) to viii), wherein R ¹ is —N (CH ₃ ) ₂ .

x) In another embodiment, the present invention relates to compounds of formula I corresponding to any of embodiments iv) to viii), wherein R ¹ is —NCH ₃ (CH ₂ CH ₂ OH).

xi) In another embodiment, the present invention relates to compounds of formula I corresponding to any of embodiments iv) to x), wherein R ² is ethyl, isopropyl, tert-butyl, ethoxy, n-propoxy or isopropoxy.

xii) In another embodiment, the present invention relates to compounds of formula I according to Embodiment xi), in which R ² is isopropoxy.

xiii) In another embodiment, the present invention relates to compounds of formula I corresponding to any of embodiments iv) to x), wherein R ² is trifluoromethyl, difluoromethoxy, methylsulfonyl or acetylamino.

xiv) In another embodiment, the present invention relates to compounds of formula I, corresponding to any of embodiments iv) to x), in which R ² is a methoxy group.

xv) In another embodiment, the present invention relates to compounds of formula I corresponding to any of embodiments iv) to x), wherein R ² is hydrogen, methyl, n-propyl, cyano, halogen or acetyl.

The term "halogen" as used in the present invention means fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine.

If the compounds, salts, pharmaceutical compositions, diseases, and the like are indicated in the plural, this also means a single compound, salt, and the like.

Any indication of a compound of Formula I above and below in the present invention should be understood to refer to salts, preferably pharmaceutically acceptable salts of a compound of Formula I, if this is suitable or appropriate.

The term “pharmaceutically acceptable salts” means non-toxic addition salts with an inorganic or organic acid and / or base. See the publication "Salt selection for basic drugs". Int. J. Pharm. 1986, 33, 201-17.

The present invention also includes isotopically labeled, preferably ² H (deuterium) labeled compounds of formula I, these compounds are identical to compounds of formula I, with the difference that one or more is replaced by atoms having the same atomic number but atomic mass or mass a number different from the atomic mass or mass number commonly found in nature. Isotopically labeled, preferably labeled with ² H (deuterium) compounds of formula I and their salts are included in the scope of the present invention. Substitution of hydrogen with the heavier ² H isotope (deuterium) can lead to greater metabolic stability, leading, for example, to an increased half-life in vivo or the possibility of using smaller doses, or may lead to a decrease in the inhibition of P450 cytochrome enzymes, leading, for example, to improved security profile. In one embodiment of the present invention, the compounds of formula I are not isotopically labeled or they are labeled with only one or more deuterium atoms. In one embodiment, the compounds of formula I are not isotopically labeled at all. Isotope-labeled compounds of formula I can be prepared by methods similar to those described below in the present invention, but using appropriate isotopically substituted variants of suitable reagents or starting materials.

Examples of preferred compounds of formula I are selected from the group consisting of:

(S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- {1-benzyl-2- [4- (4-dimethylaminobenzyl) piperazin-1-yl] -2-oxoethyl } -3- (4-trifluoromethylphenyl) acrylamide,

(S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- {1-benzyl-2- [4- (4-dimethylaminobenzyl) piperazin-1-yl] -2-oxoethyl } -3- (6-trifluoromethylpyridin-3-yl) -acrylamide,

(S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- {1-benzyl-2- [4- (4-dimethylaminobenzyl) piperazin-1-yl] -2-oxoethyl } -3- (6-methoxypyridin-3-yl) acrylamide,

(S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- {1-benzyl-2- [4- (4-dimethylaminobenzyl) piperazin-1-yl] -2-oxoethyl } -3- (6-ethoxypyridin-3-yl) acrylamide,

(S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- {1-benzyl-2- [4- (4-dimethylaminobenzyl) piperazin-1-yl] -2-oxoethyl } -3- (4-ethoxyphenyl) acrylamide,

(S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- {1-benzyl-2- [4- (4-dimethylaminobenzyl) piperazin-1-yl] -2-oxoethyl } -3- (4-methanesulfonylphenyl) acrylamide,

(S) -3- (4-Acetylaminophenyl) -N- [4- (4-acetylpiperazin-1-yl) benzyl] -N- {1-benzyl-2- [4- (4-dimethylaminobenzyl) piperazine- 1-yl] -2-oxoethyl} acrylamide,

(S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- {1-benzyl-2- [4- (4-dimethylaminobenzyl) piperazin-1-yl] -2-oxoethyl } -3- (4-propoxyphenyl) acrylamide,

(S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- {1-benzyl-2- [4- (4-dimethylaminobenzyl) piperazin-1-yl] -2-oxoethyl } -3- (4-isopropoxyphenyl) acrylamide,

(S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- {1-benzyl-2- [4- (4-dimethylaminobenzyl) piperazin-1-yl] -2-oxoethyl } -3- (4-ethylphenyl) acrylamide,

(S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- {1-benzyl-2- [4- (4-dimethylaminobenzyl) piperazin-1-yl] -2-oxoethyl } -3- (4-difluoromethoxyphenyl) acrylamide,

(S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- {1-benzyl-2- [4- (4-dimethylaminobenzyl) piperazin-1-yl] -2-oxoethyl } -3- (4-tert-butylphenyl) acrylamide,

(S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- {1-benzyl-2- [4- (4-dimethylaminobenzyl) piperazin-1-yl] -2-oxoethyl } -3- (4-isopropylphenyl) acrylamide,

(S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- [1-benzyl-2- (4- {4 - [(2-hydroxyethyl) methylamino] benzyl} - piperazin-1-yl) -2-oxoethyl] -3- (4-trifluoromethylphenyl) acrylamide,

(S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- [1-benzyl-2- (4- {4 - [(2-hydroxyethyl) methylamino] benzyl} - piperazin-1-yl) -2-oxoethyl] -3- (6-trifluoromethylpyridin-3-yl) acrylamide,

(S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- [1-benzyl-2- (4- {4 - [(2-hydroxyethyl) methylamino] benzyl} - piperazin-1-yl) -2-oxoethyl] -3- (6-methoxypyridin-3-yl) acrylamide,

(S) -N- [4- (4-Acetylpiperisin-1-yl) benzyl] -N- [1-benzyl-2- (4- {4 - [(2-hydroxyethyl) methylamino] benzyl} - piperazin-1-yl) -2-oxoethyl] -3- (6-ethoxypyridin-3-yl) acrylamide,

(S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- [1-benzyl-2- (4- {4 - [(2-hydroxyethyl) methylamino] benzyl} - piperazin-1-yl) -2-oxoethyl] -3- (4-ethoxyphenyl) acrylamide,

(S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- [1-benzyl-2- (4- {4 - [(2-hydroxyethyl) methylamino] benzyl} - piperazin-1-yl) -2-oxoethyl] -3- (4-methanesulfonylphenyl) acrylamide,

(S) -3- (4-Acetylaminophenyl) -N- [4- (4-acetylpiperazin-1-yl) benzyl] -N- [1-benzyl-2- (4- {4 - [(2-hydroxyethyl ) -methylamino] -benzyl} -piperazin-1-yl) -2-oxoethyl] acrylamide,

(S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- [1-benzyl-2- (4- {4 - [(2-hydroxyethyl) methylamino] benzyl} - piperazin-1-yl) -2-oxoethyl] -3- (4-propoxyphenyl) acrylamide,

(S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- [1-benzyl-2- (4- {4 - [(2-hydroxyethyl) methylamino] benzyl} - piperazin-1-yl) -2-oxoethyl] -3- (4-isopropoxyphenyl) acrylamide,

(S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- [1-benzyl-2- (4- {4 - [(2-hydroxyethyl) methylamino] benzyl} - piperazin-1-yl) -2-oxoethyl] -3- (4-ethylphenyl) acrylamide,

(S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- [1-benzyl-2- (4- {4 - [(2-hydroxyethyl) methylamino] benzyl} - piperazin-1-yl) -2-oxoethyl] -3- (4-difluoromethoxyphenyl) acrylamide,

(S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- [1-benzyl-2- (4- {4 - [(2-hydroxyethyl) methylamino] benzyl} - piperazin-1-yl) -2-oxoethyl] -3- (4-isopropylphenyl) acrylamide,

(S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- [1-benzyl-2- (4- {4 - [(2-hydroxyethyl) methylamino] benzyl} - piperazin-1-yl) -2-oxoethyl] -3- (4-tert-butylphenyl) acrylamide, and

(S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- {1-benzyl-2- [4- (4-nitrobenzyl) piperazin-1-yl] -2-oxoethyl } -3- (4-trifluoromethylphenyl) acrylamide.

Additional examples of preferred compounds of formula I are selected from the group consisting of:

(S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- {1- (4- (4- (dimethylamino) benzyl) piperazin-1-yl) -1-oxo-3- phenylpropan-2-yl} cinnamide,

(S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- {1- [4- (4- (dimethylamino) benzyl) piperazin-1-yl] -1-oxo-3- phenylpropan-2-yl} -3- (p-tolyl) acrylamide,

(S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- {1- (4- (4- (dimethylamino) benzyl) piperazin-1-yl) -1-oxo-3- phenylpropan-2-yl} -3- (4-propylphenyl) acrylamide,

(S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- {1- (4- (4- (dimethylamino) benzyl) piperazin-1-yl) -1-oxo-3- phenylpropan-2-yl} -3- (4-methoxyphenyl) acrylamide,

(S) -3- (4-Acetylphenyl) -N- [4- (4-acetylpiperazin-1-yl) benzyl] -N- {1- (4- (4- (dimethylamino) benzyl) piperazin-1-yl ) -1-oxo-3-phenylpropan-2-yl} acrylamide,

(S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -3- (4-cyanophenyl) -N- {1- (4- (4- (dimethylamino) benzyl) piperazin-1-yl ) -1-oxo-3-phenylpropan-2-yl} acrylamide,

(S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- {1- (4- (4- (dimethylamino) benzyl) piperazin-1-yl) -1-oxo-3- phenylpropan-2-yl} -3- (4-fluorophenyl) acrylamide, and

(S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -3- (4-chlorophenyl) -N- {1- (4- (4- (dimethylamino) benzyl) piperazin-1-yl ) -1-oxo-3-phenylpropan-2-yl} acrylamide.

Additional examples of preferred compounds of formula I are selected from the group consisting of:

(S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- [1-benzyl-2- (4-benzylpiperazin-1-yl) -2-oxoethyl] -3- (4 ethyl phenyl) acrylamide,

(S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- [1-benzyl-2- (4-benzylpiperazin-1-yl) -2-oxoethyl] -3- (4 tert-butylphenyl) acrylamide,

(S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- [1-benzyl-2- (4-benzylpiperazin-1-yl) -2-oxoethyl] -3- (4 ethoxyphenyl) acrylamide,

(S) -4- (2 - {[4- (4-acetylpiperazin-1-yl) benzyl] - [1-benzyl-2- (4-benzylpiperazin-1-yl) -2-oxoethyl] methyl ester - carbamoyl} -vinyl) -benzoic acid,

(S) -N- [4- (4-Acetylpiperisin-1-yl) benzyl] -N- [1-benzyl-2- (4-benzylpiperidin-1-yl) -2-oxoethyl] -3- (4 methanesulfonylphenyl) acrylamide,

(S) -3- (4-Acetylaminophenyl) -N- [4- (4-acetylpiperazin-1-yl) benzyl] -N- [1-benzyl-2- (4-benzylpiperazin-1-yl) -2 -oxoethyl] -acrylamide,

(S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- [1-benzyl-2- (4-benzylpiperazin-1-yl) -2-oxoethyl] -3- (4 propoxyphenyl) acrylamide,

(S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- [1-benzyl-2- (4-benzylpiperazin-1-yl) -2-oxoethyl] -3- (4 isopropoxyphenyl) acrylamide,

(S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- [1-benzyl-2- (4-benzylpiperazin-1-yl) -2-oxoethyl] -3- (4 isopropylphenyl) acrylamide,

(S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- {1-benzyl-2- [4- (4-cyanobenzyl) piperazin-1-yl] -2-oxoethyl } -3- (4-trifluoromethylphenyl) acrylamide,

(S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- {1-benzyl-2- [4- (4-cyanobenzyl) piperazin-1-yl] -2-oxoethyl } -3- (4-ethoxyphenyl) acrylamide,

(S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- {1-benzyl-2- [4- (4-cyanobenzyl) piperazin-1-yl] -2-oxoethyl } -3- (4-methanesulfonylphenyl) acrylamide,

(S) -3- (4-Acetylaminophenyl) -N- [4- (4-acetylpiperazin-1-yl) benzyl] -N- {1-benzyl-2- [4- (4-cyanobenzyl) piperazine- 1-yl] -2-oxoethyl} acrylamide,

(S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- {1-benzyl-2- [4- (4-cyanobenzyl) piperazin-1-yl] -2-oxoethyl } -3- (4-propoxyphenyl) acrylamide,

(S) -N- [4- (4-Acetyliperazin-1-yl) benzyl] -N- {1-6enzyl-2- [4- (4-cyanobenzyl) piperazin-1-yl] -2-oxoethyl } -3- (4-isopropoxyphenyl) acrylamide,

(S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- {1-benzyl-2- [4- (4-cyanobenzyl) piperazin-1-yl] -2-oxoethyl } -3- (4-ethylphenyl) acrylamide,

(S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- {1-benzyl-2- [4- (4-cyanobenzyl) piperazin-1-yl] -2-oxoethyl } -3- (4-difluoromethoxyphenyl) acrylamide,

(S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- {1-benzyl-2- [4- (4-cyanobenzyl) piperazin-1-yl] -2-oxoethyl } -3- (4-isopropylphenyl) acrylamide,

(S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- {1-benzyl-2- [4- (4-cyanobenzyl) piperazin-1-yl] -2-oxoethyl } -3- (4-trifluoromethoxyphenyl) acrylamide,

(S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- {1-benzyl-2- [4- (4-cyanobenzyl) piperazin-1-yl] -2-oxoethyl } -3- (4-tert-butylphenyl) acrylamide,

(S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- {1-benzyl-2- [4- (4-chlorobenzyl) piperazin-1-yl] -2-oxoethyl } -3- (4-ethoxyphenyl) acrylamide,

(S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- {1-benzyl-2- [4- (4-chlorobenzyl) piperazin-1-yl] -2-oxoethyl } -3- (4-methanesulfonylphenyl) acrylamide,

(S) -3- (4-Acetylaminophenyl) -N- [4- (4-acetylpiperazin-1-yl) benzyl] -N- {1-benzyl-2- [4- (4-chlorobenzyl) piperazine- 1-yl] -2-oxoethyl} acrylamide,

(S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- {1-benzyl-2- [4- (4-chlorobenzyl) piperazin-1-yl] -2-oxoethyl } -3- (4-propoxyphenyl) acrylamide,

(S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- {1-benzyl-2- [4- (4-chlorobenzyl) piperazin-1-yl] -2-oxoethyl } -3- (4-isopropoxyphenyl) acrylamide,

(S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- {1-benzyl-2- [4- (4-chlorobenzyl) piperazin-1-yl] -2-oxoethyl } -3- (4-ethylphenyl) acrylamide,

(S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- {1-benzyl-2- [4- (4-chlorobenzyl) piperazin-1-yl] -2-oxoethyl } -3- (4-difluoromethoxyphenyl) acrylamide,

(S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- {1-benzyl-2- [4- (4-chlorobenzyl) piperazin-1-yl] -2-oxoethyl } -3- (4-isopropylphenyl) acrylamide,

(S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- {1-benzyl-2- [4- (4-chlorobenzyl) piperazin-1-yl] -2-oxoethyl } -3- (4-tert-butylphenyl) acrylamide,

(S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- {1-benzyl-2- [4- (4-methoxybenzyl) piperazin-1-yl] -2-oxoethyl } -3- (4-trifluoromethylphenyl) acrylamide, and

(S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- {1-benzyl-2- [4- (4-isopropoxybenzyl) piperazin-1-yl] -2-oxoethyl } -3- (4-trifluoromethylphenyl) acrylamide.

Additional examples of preferred compounds of formula I are selected from the group consisting of:

(S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- {1-benzyl-2- [4- (4- (methylsulfonyl) benzyl) piperazin-1-yl] -2-oxoethyl} -3- (4-isopropoxyphenyl) acrylamide,

(S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- {1-benzyl-2- [4- (4- (methylsulfonyl) benzyl) piperazin-1-yl] -2-oxoethyl} -3- (4-tert-butylphenyl) acrylamide,

(S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- {1-benzyl-2- [4- (4- (methylsulfonyl) benzyl) piperazin-1-yl] -2-oxoethyl} -3- (4-propoxyphenyl) acrylamide,

(S) -N- (4- (4-Acetylpiperazin-1-yl) benzyl) -N- (1- (4- (4- (methylsulfonyl) benzyl) piperazin-1-yl) -1-oxo-3- phenylpropan-2-yl) -3- (4- (trifluoromethyl) phenyl) acrylamide,

(S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- {1-benzyl-2- [4- (4- (ethylsulfonyl) benzyl) piperazin-1-yl] -2-oxoethyl} -3- (4-propoxyphenyl) acrylamide, and

(S) -N- (4- (4-Acetylpiperazin-1-yl) benzyl) -N- (1- (4- (4- (ethylsulfonyl) benzyl) piperazin-1-yl) -1-oxo-3- phenylpropan-2-yl) -3- (4- (trifluoromethyl) phenyl) acrylamide.

The compounds of formula I and their pharmaceutically acceptable salts can be used as medicaments, for example, in the form of pharmaceutical compositions intended for enteral or parenteral administration, and they are suitable for the treatment and / or prevention of the diseases described in the present invention, preferably such as malaria.

The preparation of pharmaceutical compositions can be carried out by methods that should be known to any person skilled in the art (see, for example, Remington, The Science and Practice of Pharmacy, 21 st Edition (2005), Part 5, "Pharmaceutical Manufacturing" [published by Lippincott Williams & Wilkins]), by introducing the described compounds of formula I or their pharmaceutically acceptable salts, optionally in combination with other therapeutically useful substances, into a galenic administration form together with suitable non-toxic inert pharmaceutically acceptable solid or liquid carriers and If necessary, with conventional pharmaceutical excipients.

In one embodiment, the present invention relates to a method for treating or preventing diseases of the invention, preferably such as malaria, said method comprising administering to a subject a compound of formula I in a pharmaceutically active amount.

The compounds of formula I or the above pharmaceutical compositions can also be used in combination with one or more other therapeutically useful substances, for example, other anti-malarial drugs such as quinolines (e.g. quinine, chloroquine, amodiaquine, mefloquine, primaquine and tafenoquine), peroxide antimalarials (e.g. artemisinin, artemether and artesunate), pyrimethamine sulfadoxine antimalarials (e.g. fansidar®), hydroxy naphthoquinones (e.g. atovaquone), anti-malaria s means of acridine type (e.g., pironaridin) protivoprotozoynymi and other means such as etilstibamin, gidroksistilbamidin, pentamidine, stilbamidine, hinapiramin, puromycin propamidin, nifurtimox, melarsoprol, nimorazole, nifuroksim, aminitrozol etc.

The present invention also relates to the use of a compound of formula I for the preparation of a pharmaceutical composition, optionally intended for use in combination with one or more other therapeutically useful substances, such as those mentioned in the previous paragraph, for the prevention and / or treatment of the diseases specified in the present invention , preferably such as malaria.

The compounds of formula I proposed in the present invention can be obtained by the methods described in the present invention, preferably as described in the experimental section.

Typically, all chemical transformations can be carried out in accordance with well-known standard methodologies or as described in the following procedures.

Obtaining compounds of formula I, with the exception of compounds in which R ¹ is —NCH ₃ (CH ₂ CH ₂ OH):

Boc-Phe-OH 1 can be coupled with a benzylpiperazine 2 derivative via a coupling reaction to form a peptide using activating reagents such as TBTU (or PyBOP / HOBt) in the presence of a base such as DIPEA (or NEM) in DCM (or DMF) at RT and obtain intermediate 3. Alternatively, Cbz-Phe-OH can also be used to prepare compound 3 at the initial stage of the coupling reaction to form a peptide. Removal of the Boc protecting group is usually carried out by reacting compound 3 with 4N. a solution of HCl in dioxane using DCM as a solvent, while the removal of the Cbz protecting group is carried out by hydrogenation with a Pd / C catalyst in MeOH to give intermediate amine 4. The reductive amination of free amine 4 and aldehyde 5 in MeOH is carried out by boiling with a reflux condenser, gives an unstable imine (not shown in the diagram), which is then reduced with NaBH ₄ at RT and an intermediate secondary amine 6 is obtained. Alternatively, reductive amination can be carried out in solution an agent, such as CH ₃ CN, in the presence of a reducing reagent, such as NaBH (OAc) ₃ , and obtain the desired intermediate secondary amine 6. Then, compound 6 can be introduced into the coupling reaction with carboxylic acid 7 using a coupling reaction reagent to form a peptide such as TBTU, PyBOP / HOBt, or Gosez's reagent, in a solvent such as DCM (or DMF), at RT in the presence of a base such as DIPEA (or NEM). Alternatively, carboxylic acid 7 can be converted to the corresponding acid chloride (not shown in the diagram) using oxalyl chloride in DCM to give the final compounds 8 of formula I.

In the case where R ¹ = —NCH ₃ (CH ₂ CH ₂ OH), the compounds of formula I are prepared according to Scheme 2.

Boc-Phe-OH 1 is coupled with a benzylpiperazine 9 derivative via a coupling reaction to form a peptide using activating reagents such as TBTU (or PyBOP / HOBt) in the presence of a base such as DIPEA (or NEM) in DCM ( or DMF) at RT and intermediate 10 is obtained. Alternatively, Cbz-Phe-OH can also be used to prepare compound 10 at the initial stage of the coupling reaction to form a peptide. Boc deprotection is usually carried out by reacting compound 10 with 4 N. a solution of HCl in dioxane using DCM as a solvent, while the removal of the Cbz protecting group is carried out by hydrogenation with a Pd / C catalyst in MeOH to give intermediate amine 11. The reductive amination of the free amine 11 and aldehyde 5 in CH ₃ CN at RT in the presence of a reducing reagent such as NaBH (OAc) ₃ provides an intermediate secondary amine 12. The free hydroxy group of compound 12 is protected using a silylating agent, for example, TBDMSC1, to give compound 13, which is e is then introduced into the coupling reaction with a carboxylic acid 7 using a reagent coupling reaction to form a peptide, such as TBTU (or PyBOP / HOBt), in a solvent such as DCM (or DMF) at RT in the presence of a base such as DIPEA. Alternatively, carboxylic acid 7 can be activated by conversion to the corresponding acid chloride (not shown in the diagram) with oxalyl chloride in DCM and then compound 14. Subsequent removal of the protective group in a slightly acidic medium, such as a 1 M aqueous solution of HCl in MeOH, or using fluorine-containing reagents, such as TBAF, gives the final compounds 16 of formula I.

The compounds of formula I can also be obtained in accordance with the synthesis pathway shown in Scheme 3.

The reductive amination reaction of amino acid H-Phe-OMe.HCl 17 and aldehyde 5 in MeOH, carried out under reflux, gives the corresponding imine, which is then reduced in the presence of a reducing reagent, such as NaBH4, at RT and a secondary amine 18 is obtained. Compound 18 can also be prepared using the conditions described above to prepare compounds 6 and 12. Then, ester 18 is coupled with acid chloride 19 derived from carboxylic acid 7 using oxalyl chloride in DCM or reagent that Goseza. Alternatively, compound 18 can be directly introduced into the coupling reaction with carboxylic acid 7 through a coupling reaction to form a peptide using TBTU (or PyBOP / HOBt) as a reagent in a solvent such as DCM (or DMF), in CT in the presence of a base, such as DIPEA (or NEM). A carefully conducted saponification reaction of ester 20 with 0.5 N. an aqueous solution of LiOH in THF, carried out at 0 ° C, gives acid 21. The final coupling reaction to form a peptide with benzylpiperazine 2 gives the final compounds 8 of formula I.

Benzylpiperazines 2 and 9 are commercially available and / or can be synthesized according to synthesis scheme 4 below:

Cinnamic acids 7 are commercially available and / or can be synthesized as described below by synthesis:

Way A: Knevenagel Reaction

Cinnamic acids 7 are obtained by refluxing aldehyde 25 with malonic acid in a piperidine / pyridine mixture (WO 00/66566).

Path B: Horner-Emmons Reaction

Cinnamic acids 7 are obtained in two stages by the reaction of aldehydes 25 with triethylphosphonoacetate 26 in the presence of a base such as NaH in an aprotic solvent such as THF, followed by saponification of the resulting ethyl ester with 4N. a solution of KOH in EtOH.

The following examples illustrate the present invention. All temperatures are given in degrees Celsius and pressures are given in mbar. Unless otherwise indicated, reactions occur during CT. The ratios of solvent quantities to each other are always indicated as volume ratios. The chemical names of the final products and intermediates are derived from chemical structural formulas using the ChemDrawPro Automatic Nomenclature program.

Analytical HPLC conditions:

(I) Agilent 1100 series, detection: UV / view, and MS (MS: Thermo Finnigan with one quadrupole lens). Columns (4.6 × 50 mm, 5 μm): Waters X-Bridge C 18 or Waters Atlantis T3.

Carrying out in alkaline medium: Eluents: A: MeCN, B: concentrated NH ₃ in water (1.0 ml / l). Gradient mode: from 5 to 95% in 1.5 minutes. Flow rate: 4.5 ml / min.

Carrying out in an acidic environment: Eluents: A: water + 0.04% TFA, B: MeCN. Gradient mode: from 5 to 95% in 1.5 minutes. Flow rate: 4.5 ml / min.

Preparative HPLC conditions:

Gilson detection: UV / view. + MS or UV / view. + IDRS.

Carrying out in an alkaline environment: Eluents: A: MeCN, B: H ₂ O + 0.5% NH ₃ (25% aqueous solution).

(II) column Waters X-Bridge, 19 × 50 mm, 5 μm. Gradient mode: from 20 to 90% A in 5 minutes Flow rate: 40 ml / min.

(III) column Waters X-Bridge, 30 × 75 mm, 10 μm. Gradient mode: from 20 to 90% A in 6 min. Flow rate: 75 ml / min.

The following abbreviations are used in the present invention:

AcOH acetic acid Boc tert-butoxycarbonyl Boc-phe-oh Boc-l-phenylalanine Cbz benzyloxycarbonyl Cbz-phe-oh Cbz-l-phenylalanine DXM dichloromethane DIPEA N, N-diisopropylethylamine DMF N, N-dimethylformamide Et ethyl EtOH ethanol EtOAc ethyl acetate Ei20 diethyl ether IDRS light scattering evaporative detection h clock) Hobt hydroxybenzotriazole H-Phe-OMe.HCl L-phenylalanine methyl ester hydrochloride HPLC high performance liquid chromatography LC-MS liquid chromatography - mass spectroscopy Me methyl Meoh methanol min minute (s) MS mass spectroscopy NaBH (OAc) ₃ sodium triacetoxyborohydride Nem N-ethylmorpholine PFF phosphate buffered saline Pd / c palladium on charcoal PG protective group

Pybop benzotriazol-1-yloxy-tris-pyrrolidinophosphonium hexafluorophosphate CT room temperature Rt retention time of the substance in HPLC (min) TBAF tetra-n-butylammonium fluoride TBDMSC1 tert-butyldimethylchlorosilane TBTU O-benzotriazol-1-yl-N, N, N ', N'-tetramethyluronium tetrafluoroborate TFK trifluoroacetic acid THF tetrahydrofuran UV ultraviolet radiation View. visible radiation

Obtaining compounds of formula I by the synthesis pathway shown in Scheme 1 - general methods and examples:

General Procedure A - Stage 1

While stirring, to a suspension of 1 mmol of Boc-Phe-OH or Cbz-Phe-OH in 0.6 ml of dry DCM (or DMF) in a nitrogen atmosphere, 1 mmol of TBTU and 2 mmol of NEM are successively added. The resulting light yellow suspension was stirred at RT for 1 h, then 1 mmol of benzylpiperazine in 0.25 ml of dry DCM (or DMF) was added. The resulting reaction mixture was further stirred at RT overnight. After stirring was complete, the reaction mixture was diluted with DCM and the reaction was stopped with saturated NaHCO ₃ solution. The aqueous phase is extracted with DCM (x3), the combined organic phases are washed successively with H ₂ O and brine, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO ₂ 60F) to give the title compound. Intermediates 1

R ¹ / PG Chemical name Exit LC-MS Rt (min) [M + H] ⁺ H / boc (S) - [1-benzyl-2- (4-benzylpiperazin-1-yl) -2-oxoethyl] carbamic acid tert-butyl ester Quantitative 0.98 * 424.22 CN / Boc (S) - {1-benzyl-2- [4- (4-cyanobenzyl) piperazin-1-yl] -2-oxoethyl} carbamic acid tert-butyl ester 94% 0.92 * 449.12 N (CH ₃ ) ₂ / Boc (S) - {1-benzyl-2- [4- (4-dimethylaminobenzyl) piperazin-1-yl] -2-oxoethyl} carbamic acid tert-butyl ester Quantitative 0.96 * 467.23 Cl / boc (S) - {1-benzyl-2- [4- (4-chlorobenzyl) piperazin-1-yl] -2-oxoethyl} -carbamic acid tert-butyl ester Quantitative 1.01 * 457.79 S (O ₂ ) Me / Cbz (S) -Benzyl- (1- (4- (4- (methylsulfonyl) benzyl) piperazin-yl) -1-oxo-3-phenylpropan-2-yl) carbamate 76% 0.62 ** 536.16 S (O ₂ ) Et / Cbz (S) -Benzyl- (1- (4- (4- (ethylsulfonyl) benzyl) piperazin-1-yl) -1-oxo-3-phenylpropan-2-yl) carbamate 47% 0.64 ** 550.17 * analytical HPLC I, column X-Bridge, alkaline medium. ** analytical HPLC, Waters Atlantis T3 column, acidic medium General procedure B - step 2

Scheme 8

If PG = Boc:

To a solution of 1 mmol containing a Voe protecting group of amine in 9 ml of dry DCM at 0 ° C., 4.5 ml of 4N are added dropwise. a solution of HCl in dioxane. The resulting reaction mixture was stirred under nitrogen at RT for 4 h, cooled to 0 ° C and carefully neutralized with 1 N aqueous NaOH to pH = 7. The aqueous phase is then extracted with DCM (x3). The combined organic phases are washed successively with H ₂ O and brine, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a free primary amine, which is used in the next step without further purification.

If PG = Cbz:

A mixture of 2 mmol of a protecting group Cbz amine, 10% Pd-C (100 mg) in dry EtOH (25 ml) was stirred under a hydrogen atmosphere at RT for 3 hours. The reaction mixture was filtered through celite and concentrated under reduced pressure to obtain a free primary the amine that is used in the next step without further purification.

Intermediates 2

R ¹ Chemical name Exit LC-MS Rt (min) [M + H] ⁺ N (S) -2-amino-1- (4-benzylpiperazin-1-yl) -3-phenylpropan-1-one Quantitative 0.79 * 324.29 CN (S) -4- [4- (2-amino-3-phenylpropionyl) piperazin-1-methylmethyl] benzonitrile Quantitative 0.74 * 349.16 N (CH3) 2 (S) -2-amino-1- [4- (4-dimethylaminobenzyl) piperazin-1-yl] -3-phenylpropan-1-one Quantitative 0.78 * 367.19 Cl (S) -2-amino-1- [4- (4-chlorobenzyl) piperazin-1-yl] -3-phenylpropan-1-one Quantitative 0.82 * 358.11 S (O ₂ ) Me (S) -2-amino-1- (4- (4- (methylsulfonyl) benzyl) pipeperazin-1-yl) -3-phenylpropan-1-one 89% 0.37 ** 401.79 S (O ₂ ) Et (S) -2-amino-1- (4- (4- (ethylsulfonyl) benzyl) piperazin-1-yl) -3-phenylpropan-1-one 88% 0.4 ** 416.07 * analytical HPLC I, column X-Bridge, alkaline medium. ** analytical HPLC, Waters Atlantis T3 column, acidic medium

General procedures C1 and C2 - stage 3

General procedure C1:

A solution of 1 mmol of amine and 1 mmol of aldehyde in 5 ml of dry MeOH in a nitrogen atmosphere is refluxed for 24 hours. Then, the resulting mixture is cooled to CT, then 1.5 mmol of NaBH _{4 is} added portionwise. The resulting heterogeneous mixture was further stirred at RT for 2 h, the reaction was stopped with saturated aqueous NaHCO ₃ and the mixture was extracted with EtOAc (x3). The combined organic phases are washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO ₂ 60F) to give the title compound.

General procedure C2:

To a solution of 1 mmol of amine and 1 mmol of aldehyde in 5 ml of dry CH ₃ CN, 1.5 mmol of NaBH (OAc) _{3 is} added in portions. The resulting heterogeneous mixture was further stirred at RT for 4 hours, the reaction was stopped with saturated aqueous NaHCO ₃ and the mixture was extracted with EtOAc (x3). The combined organic phases are washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO ₂ 60F) to give the title compound.

Intermediates 3

R ¹ Chemical name Exit LC-MS Rt (min) [M + H] ⁺ N (S) -2- [4- (4-Acetylpiperazin-1-yl) benzylamino] -1- (4-benzylpiperazin-1-yl) -3-phenylpropan-1-one 77% 0.84 * 540.30 CN (S) -4- (4- {2- [4- (4-Acetylpiperazin-1-yl) benzylamino] -3-phenylpropionyl} piperazin-1-methylmethyl) benzonitrile 81% 0.79 * 565.16 N (CH ₃ ) ₂ (S) -2- [4- (4-Acetylpiperazin-1-yl) benzylamino] -1- [4- (4-dimethylaminobenzyl) piperazin-1-yl] -3-phenylpropan-1-one 64% 0.83 * 583.20 Cl (S) -2- [4- (4-Acetylpiperazin-1-yl) benzylamino] -1- [4- (4-chlorobenzyl) piperazin-1-yl] -3-phenylpropan-1-one 76% 0.88 * 574.10 S (O ₂ ) Me (S) -2- [4- (4-Acetylpiperazin-1-yl) benzylamino] -1- [4- (4-methylsulfonylbenzyl) piperazin-1-yl] -3-phenylpropan-1-one 52% 0.43 ** 618.22 S (O ₂ ) Et (S) -2- [4- (4-Acetylpiperazin-1-yl) benzylamino] -1- [4- (4-ethylsulfonylbenzyl) piperazin-1-yl] -3-phenylpropan-1-one 80% 0.45 ** 632.2 * analytical HPLC I, column X-Bridge, alkaline medium. ** analytical HPLC, Waters Atlantis T3 column, acidic medium General procedures D1 and D2 - stage 4

General procedure D1:

To a solution of 1 mmol of cinnamic acid in 5 ml of dry DCM in a nitrogen atmosphere, 1.4 mmol of 1-chloro-N, N-2-trimethylpropenylamine (Gosez's reagent) is added. The resulting mixture was stirred at RT for 1 h, then a solution of 1 mmol of amine and 3 mmol of DIPEA in 4 ml of dry DCM was added. The reaction mixture was further stirred at RT overnight. After stirring was complete, a saturated aqueous MAHCO3 solution was added and the mixture was extracted with DCM (x3). The combined organic phases are washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO ₂ 60F) or by preparative HPLC to give the final compound.

General procedure D2:

To a solution (or suspension) of 1.05 mmol of cinnamic acid in 3.5 ml of dry DCM in a nitrogen atmosphere at 0 ° C, add 1.1 mmol of oxalyl chloride and 3 drops of DMF. The resulting mixture was stirred at RT for 1 h, cooled to 0 ° C, then a solution of 1 mmol of amine and 2 mmol of DIPEA in 3 ml of dry DCM was added. The reaction mixture was further stirred at RT overnight. After stirring was complete, a saturated aqueous solution of NaHCO _{3 was} added and the mixture was extracted with DCM (x3). The combined organic phases are washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO ₂ 60F) or by preparative HPLC to give the final compound.

Compound of Example No. Chemical name LC-MS Rt (min) [M + H] ⁺ one** (S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- [1-benzyl-2- (4-benzylpiperazin-1-yl) -2-oxoethyl] -3- (4 trifluoromethylphenyl) acrylamide 1.00 * 738.37 2 (S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- [1-benzyl-2- (4-benzylpiperazin-1-yl) -2-oxoethyl] -3- (4 ethyl phenyl) acrylamide 1.02 * 698.45 3 (S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- [1-benzyl-2- (4-benzylpiperazin-1-yl) -2-oxoethyl] -3- (4 tert-butylphenyl) acrylamide 1.06 * 726.46

Compound of Example No. Chemical name LC-MS Rt (min) [M + H] ⁺ four (S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- [1-benzyl-2- (4-benzylpiperazin-1-yl) -2-oxoethyl] -3- (4 ethoxyphenyl) acrylamide 0.98 * 714.26 5 (S) -4- (2 - {[4- (4-acetylpiperazin-1-yl) benzyl] - [1-benzyl-2- (4-benzylpiperazin-1-yl) -2-oxoethyl] methyl ester - carbamoyl} -vinyl) -benzoic acid 0.94 * 728.39 6 (S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- [1-benzyl-2- (4-benzylpiperazin-1-yl) -2-oxoethyl] -3- (4 methanesulfonylphenyl) acrylamide 0.88 * 748.36 7 (S) -3- (4-Acetylaminophenyl) -N- [4- (4-acetylpiperazin-1-yl) benzyl] -N- [1-benzyl-2- (4-benzylpiperazin-1-yl) -2 -oxoethyl] -acrylamide 0.86 * 727.37 8 (S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- [1-benzyl-2- (4-benzylpiperazin-1-yl) -2-oxoethyl] -3- (4 propoxyphenyl) acrylamide 1.02 * 728.40 9 (S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- [1-benzyl-2- (4-benzylpiperazin-1-yl) -2-oxoethyl] -3- (4 isopropoxyphenyl) acrylamide 1.00 * 728.43 10 (S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- [1-benzyl-2- (4-benzylpiperazin-1-yl) -2-oxoethyl] -3- (4 isopropylphenyl) acrylamide 1.05 * 712.28 eleven (S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- {1-benzyl-2- [4- (4-dimethylaminobenzyl) piperazin-1-yl] -2-oxoethyl } -3- (4-trifluoromethylphenyl) acrylamide 0.99 * 781.18 12 (S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- {1-benzyl-2- [4- (4-dimethylaminobenzyl) piperazin-1-yl] -2-oxoethyl } -3- (6-trifluoromethylpyridin-3-yl) -acrylamide 0.94 * 782.19 13 (S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- {1-benzyl-2- [4- (4-dimethylaminobenzyl) piperazin-1-yl] -2-oxoethyl } -3- (6-methoxypyridin-3-yl) acrylamide 0.91 * 744.20 fourteen (S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- {1-benzyl-2- [4- (4-dimethylaminobenzyl) piperazin-1-yl] -2-oxoethyl } -3- (6-ethoxypyridin-3-yl) acrylamide 0.94 * 758.22 fifteen (S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- {1-benzyl-2- [4- (4-dimethylaminobenzyl) piperazin-1-yl] -2-oxoethyl } -3- (4-ethoxyphenyl) acrylamide 0.97 * 757.17

Compound of Example No. Chemical name LC-MS Rt (min) [M + H] ⁺ 16 (S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- {1-benzyl-2- [4- (4-dimethylaminobenzyl) piperazin-1-yl] -2-oxoethyl } -3- (4-methanesulfonylphenyl) acrylamide 0.87 * 791.15 17 (S) -3- (4-Acetylaminophenyl) -N- [4- (4-acetylpiperazin-1-yl) benzyl] -N- {1-benzyl-2- [4- (4-dimethylaminobenzyl) piperazine- 1-yl] -2-oxoethyl} acrylamide 0.85 * 770.22 eighteen (S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- {1-benzyl-2- [4- (4-dimethylaminobenzyl) piperazin-1-yl] -2-oxoethyl } -3- (4-propoxyphenyl) acrylamide 1.00 * 771.27 19 (S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- {1-benzyl-2- [4- (4-dimethylaminobenzyl) piperazin-1-yl] -2-oxoethyl } -3- (4-isopropoxyphenyl) acrylamide 0.99 * 771.25 twenty (S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- {1-benzyl-2- [4- (4-dimethylaminobenzyl) piperazin-1-yl] -2-oxoethyl } -3- (4-ethylphenyl) acrylamide 1.00 * 741.28 21 (S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- {1-benzyl-2- [4- (4-dimethylaminobenzyl) piperazin-1-yl] -2-oxoethyl } -3- (4-difluoromethoxyphenyl) acrylamide 0.95 * 779.15 22 (S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- {1-benzyl-2- [4- (4-dimethylaminobesyl) piperazin-1-yl] -2-oxoethyl } -3- (4-tert-butylphenyl) acrylamide 1.05 * 769.26 23 (S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- {1-benzyl-2- [4- (4-dimethylaminobenzyl) piperazin-1-yl] -2-oxoethyl } -3- (4-isopropylphenyl) acrylamide 1.03 * 755.28 24 (S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- {1-benzyl-2- [4- (4-cyanobenzyl) piperazin-1-yl] -2-oxoethyl } -3- (4-trifluoromethylphenyl) acrylamide 0.96 * 763.11 25 (S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- {1-benzyl-2- [4- (4-cyanobenzyl) piperazin-1-yl] -2-oxoethyl } -3- (4-ethoxyphenyl) acrylamide 0.93 * 739.22 26 (S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- {1-benzyl-2- [4- (4-cyanobenzyl) piperazin-1-yl] -2-oxoethyl } -3- (4-methanesulfonylphenyl) acrylamide 0.84 * 773.00

Compound of Example No. Chemical name LC-MS Rt (min) [M + H] ⁺ 27 (S) -3- (4-Acetylaminophenyl) -N- [4- (4-acetylpiperazin-1-yl) benzyl] -N- {1-benzyl-2- [4- (4-cyanobenzyl) piperazine- 1-yl] -2-oxoethyl} acrylamide 0.82 * 752.02 28 (S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- {1-benzyl-2- [4- (4-cyanobenzyl) piperazin-1-yl] -2-oxoethyl } -3- (4-propoxyphenyl) acrylamide 0.97 * 753.15 29th (S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- {1-benzyl-2- [4- (4-cyanobenzyl) piperazin-1-yl] -2-oxoethyl } -3- (4-isopropoxyphenyl) acrylamide 0.96 * 753.18 thirty (S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- {1-benzyl-2- [4- (4-cyanobenzyl) piperazin-1-yl] -2-oxoethyl } -3- (4-ethylphenyl) acrylamide 0.97 * 723.19 31 (S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- {1-benzyl-2- [4- (4-cyanobenzyl) piperazin-1-yl] -2-oxoethyl } -3- (4-difluoromethoxyphenyl) acrylamide 0.92 * 761.06 32 (S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- {1-benzyl-2- [4- (4-cyanobenzyl) piperazin-1-yl] -2-oxoethyl } -3- (4-isopropylphenyl) acrylamide 0.99 * 737.23 33 (S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- {1-benzyl-2- [4- (4-cyanobenzyl) piperazin-1-yl] -2-oxoethyl } -3- (4-trifluoromethoxyphenyl) acrylamide 0.97 * 778.97 34 (S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -H- {1-benzyl-2- [4- (4-cyanobenzyl) piperazin-1-yl] -2-oxoethyl } -3- (4-tert-butylphenyl) acrylamide 1.02 * 751,21 35 (S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- {1-benzyl-2- [4- (4-chlorobenzyl) piperazin-1-yl] -2-oxoethyl } -3- (4-ethoxyphenyl) acrylamide 1.00 * 748.13 36 (S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- {1-benzyl-2- [4- (4-chlorobenzyl) piperazin-1-yl] -2-oxoethyl } -3- (4-methanesulfonylphenyl) acrylamide 0.90 * 782.11 37 (S) -3- (4-Acetylaminophenyl) -N- [4- (4-acetylpiperazin-1-yl) benzyl] -N- {1-benzyl-2- [4- (4-chlorobenzyl) piperazine- 1-yl] -2-oxoethyl} acrylamide 0.88 * 761.18

Compound of Example No. Chemical name LC-MS Rt (min) [M + H] ⁺ 38 (S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- {1-benzyl-2- [4- (4-chlorobenzyl) piperazin-1-yl] -2-oxoethyl } -3- (4-propoxyphenyl) acrylamide 1.03 * 762.18 39 (S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- {1-benzyl-2- [4- (4-chlorobenzyl) piperazin-1-yl] -2-oxoethyl } -3- (4-isopropoxyphenyl) acrylamide 1.02 * 762.13 40 (S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- {1-benzyl-2- [4- (4-chlorobenzyl) piperazin-1-yl] -2-oxoethyl } -3- (4-ethylphenyl) acrylamide 1.04 * 732.25 41 (S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -H- {1-benzyl-2- [4- (4-chlorobenzyl) piperazin-1-yl] -2-oxoethyl } -3- (4-difluoromethoxyphenyl) acrylamide 0.98 * 770.15 42 (S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- {1-benzyl-2- [4- (4-chlorobenzyl) piperazin-1-yl] -2-oxoethyl } -3- (4-isopropylphenyl) acrylamide 1.06 * 745.96 43 (S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- {1-benzyl-2- [4- (4-chlorobenzyl) piperazin-1-yl] -2-oxoethyl } -3- (4-tert-butylphenyl) acrylamide 1.08 * 760.13 44 (S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- {1-benzyl-2- [4- (4- (methylsulfonyl) benzyl) piperazin-1-yl] -2-oxoethyl} -3- (4-isopropoxyphenyl) acrylamide 0.73 *** 806.37 45 (S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- {1-benzyl-2- [4- (4- (methylsulfonyl) benzyl) piperazin-1-yl] -2-oxoethyl} -3- (4-tert-butylphenyl) acrylamide 0.78 *** 804.37 46 (S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- {1-benzyl-2- [4- (4- (methylsulfonyl) benzyl) piperazin-1-yl] -2-oxoethyl} -3- (4-propoxyphenyl) acrylamide 0.76 *** 806.37 47 (S) -N- (4- (4-Acetylpiperazin-1-yl) benzyl) -N- (1- (4- (4- (methylsulfonyl) benzyl) piperazin-1-yl) -1-oxo-3- phenylpropan-2-yl) -3- (4- (trifluoromethyl) phenyl) acrylamide 0.75 *** 816.23 48 (S) -M- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- {1-benzyl-2- [4- (4- (ethylsulfonyl) benzyl) piperazin-1-yl] -2-oxoethyl} -3- (4-propoxyphenyl) acrylamide 0.77 *** 820.43

Compound of Example No. Chemical name LC-MS Rt (min) [M + H] ⁺ 49 (S) -N- (4- (4-Acetylpiperazin-1-yl) benzyl) -N- (1- (4- (4- (ethylsulfonyl) benzyl) piperazin-1-yl) -1-oxo-3- phenylpropan-2-yl) -3- (4- (trifluoromethyl) phenyl) acrylamide 0.76 *** 829.85 * analytical HPLC I, column X-Bridge, alkaline medium. ** comparative example *** analytical HPLC, Waters Atlantis T3 column, acidic medium

Obtaining compounds of formula I by the synthesis pathway shown in Scheme 2 - general methods and examples:

Stage 1: (S) - [1-benzyl-2- (4- {4 - [(2-hydroxyethyl) methylamino] benzyl} piperazin-1-yl) -2-oxoethyl] -carbamino tert-butyl ester acids.

In accordance with General Procedure A, 60 mmoles of Boc-Phe-OH are used to obtain the desired compound in 50% yield. Rt = 0.87; [M + H] ⁺ = 497.42 (analytical HPLC I, X-Bridge column, alkaline medium).

Step 2: (S) -2-amino-1- (4- {4 - [(2-hydroxyethyl) methylamino] benzyl} piperazin-1-yl) -3-phenylpropan-1-one.

In accordance with General Procedure B, 12 mmoles of a Boe protecting group containing amine 10 are used to obtain the desired compound in quantitative yield. Rt = 0.69; [M + H] ⁺ = 397.18 (analytical HPLC I, X-Bridge column, alkaline medium).

Stage 3: (S) -2- [4- (4-Acetylpiperazin-1-yl) benzylamino] -1- (4- {4 - [(2-hydroxyethyl) methylamino] benzyl} piperazin-1- il) -3-phenylpropan-1-one.

In accordance with general procedure C2, 11.4 mmoles of free amine 11 are used to obtain the desired compound in quantitative yield. Rt = 0.74; [M + H] ⁺ = 613.24 (analytical HPLC I, X-Bridge column, alkaline medium).

General Procedure E Step 4: (S) -2- [4- (4-Acetylpiperazin-1-yl) benzylamino] -1- [4- (4 - {[2- (tert-butyldimethylsilanyloxy) ethyl] - methylamino} benzyl) piperazin-1-yl] -3-phenylpropan-1-one.

Scheme 14

3 mmol of TBDMSC1 during CT is added in portions to a solution of 1 mmol of hydroxy-containing compound 12 and 3 mmol of imidazole in 5 ml of dry DMF. The yellow solution was stirred at RT for 16 h, the reaction was stopped with H ₂ O and the mixture was extracted with EtOAc (x3). The combined organic phases are washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO ₂ 60F; DCM / MeOH, 92: 8 to 95: 5) to give the title compound as a yellow foam in 81% yield. Rt = 1.12 min; [M + H] ⁺ = 727.31. (analytical HPLC I, X-Bridge column, alkaline medium).

Stage 5

Compounds of formula 28 are prepared according to general procedures D1 or D2.

Intermediate No. Chemical name LC-MS * Rt (min) [M + H] ⁺ four (S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- {1-benzyl-2- [4- (4 - {[2- (tert-butyldimethylsilanyloxy) ethyl] - methylamine} -benzyl) piperazin-1-yl] -2-oxoethyl} -3- (4-trifluoromethylphenyl) acrylamide 1.21 925.21 5 (S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- {1-benzyl-2- [4- (4 - {[2- (tert-butyldimethylsilanyloxy) ethyl] - methylamine} -benzyl) piperazin-1-yl] -2-oxoethyl} -3- (6-trifluoromethylpyridin-3-yl) acrylamide 1.15 926.27 6 (S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- {1-benzyl-2- [4- (4 - {[2- (tert-butyldimethylsilanyloxy) ethyl] - methylamino} -benzyl) piperazin-1-yl] -2-oxoethyl} -3- (6-methoxypyridin-3-yl) acrylamide 1.14 888.29 7 (S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- {1-benzyl-2- [4- (4 - {[2- (tert-butyldimethylsilanyloxy) ethyl] - methylamino} -benzyl) piperazin-1-yl] -2-oxoethyl} -3- (6-ethoxypyridin-3-yl) acrylamide 1.19 902.33 8 (S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- {1-benzyl-2- [4- (4 - {[2- (tert-butyldimethylsilanyloxy) ethyl] - methylamino} -benzyl) piperazin-1-yl] -2-oxoethyl} -3- (4-ethoxyphenyl) acrylamide 1.20 901.29 9 (S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- {1-benzyl-2- [4- (4 - {[2- (tert-butyldimethylsilanyloxy) ethyl] - methylamino} -benzyl) piperazin-1-yl] -2-oxoethyl} -3- (4-methanesulfonylphenyl) acrylamide 1.09 935.21 10 (S) -3- (4-Acetylaminophenyl) -N- [4- (4-acetylpiperazin-1-yl) benzyl] -N- {1-benzyl-2- [4- (4 - {[2- ( tert-butyldimethylsilanyloxy) ethyl] -methylamino} benzyl) piperazin-1-yl] -2-oxoethyl} acrylamide 1,08 914.29 eleven (S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- {1-benzyl-2- [4- (4 - {[2- (tert-butyldimethylsilanyloxy) ethyl] - methylamino} -benzyl) piperazin-1-yl] -2-oxoethyl} -3- (4-propoxyphenyl) acrylamide 1.24 915.28 12 (S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- {1-benzyl-2- [4- (4 - {[2- (tert-butyldimethylsilanyloxy) ethyl] - methylamino} -benzyl) piperazin-1-yl] -2-oxoethyl} -3- (4-isopropoxyphenyl) acrylamide 1.22 915.32

Intermediate No. Chemical name LC-MS * Rt (min) [M + H] ⁺ 13 (S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- {1-benzyl-2- [4- (4 - {[2- (tert-butyldimethylsilanyloxy) ethyl] - methylamino} benzyl) piperazin-1-yl] -2-oxoethyl} -3- (4-ethylphenyl) acrylamide 1.25 885.35 fourteen (S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- {1-benzyl-2- [4- (4 - {[2- (tert-butyldimethylsilanyloxy) ethyl] - methylamino} -benzyl) piperazin-1-yl] -2-oxoethyl} -3- (4-difluoromethoxyphenyl) acrylamide 1.15 923.21 fifteen (S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- {1-benzyl-2- [4- (4 - {[2- (tert-butyldimethylsilanyloxy) ethyl] - methylamino} -benzyl) piperazin-1-yl] -2-oxoethyl} -3- (4-isopropylphenyl) acrylamide 1.29 899.32 16 (S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- {1-benzyl-2- [4- (4 - {[2- (tert-butyldimethylsilanyloxy) ethyl] - methylamino} benzyl) piperazin-1-yl] -2-oxoethyl} -3- (4-tert-butylphenyl) acrylamide 1.32 913.29 * analytical HPLC I, column X-Bridge, alkaline medium.

General Procedure F - Step 6

To a solution of 1 mmol of the protective group-containing alcohol 28 in 3.5 ml of dry THF in a nitrogen atmosphere at 0 ° C was added 3.5 mmol of TBAF (1 M solution in THF). The resulting mixture was stirred at RT for 4 hours and cooled to 0 ° C. After completion, H ₂ O was added and the mixture was extracted with DCM (x3). The combined organic phases are washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO ₂ 60F) or by preparative HPLC to give the final compound.

Compound of Example No. Chemical name LC-MS * Rt (min) [M + H] ⁺ fifty (S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- [1-benzyl-2- (4- {4 - [(2-hydroxyethyl) methylamino] benzyl} - piperazin-1-yl) -2-oxoethyl] -3- (4-trifluoromethylphenyl) acrylamide 0.91 811.21 51 (S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- [1-benzyl-2- (4- {4 - [(2-hydroxyethyl) methylamino] benzyl} - piperazin-1-yl) -2-oxoethyl] -3- (6-trifluoromethylpyridin-3-yl) acrylamide 0.86 812.24 52 (S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- [1-benzyl-2- (4- {4 - [(2-hydroxyethyl) methylamino] benzyl} - piperazin-1-yl) -2-oxoethyl] -3- (6-methoxypyridin-3-yl) acrylamide 0.82 774.25 53 (S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- [1-benzyl-2- (4- {4 - [(2-hydroxyethyl) methylamino] benzyl} - piperazin-1-yl) -2-oxoethyl] -3- (6-ethoxypyridin-3-yl) acrylamide 0.85 788.24 54 (S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- [1-benzyl-2- (4- {4 - [(2-hydroxyethyl) methylamino] benzyl} - piperazin-1-yl) -2-oxoethyl] -3- (4-ethoxyphenyl) acrylamide 0.88 787.19 55 (S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- [1-benzyl-2- (4- {4 - [(2-hydroxyethyl) methylamino] benzyl} - piperazin-1-yl) -2-oxoethyl] -3- (4-methanesulfonylphenyl) acrylamide 0.80 821.18 56 (S) -3- (4-Acetylaminophenyl) -N- [4- (4-acetylpiperazin-1-yl) benzyl] -H- [1-benzyl-2- (4- {4 - [(2-hydroxyethyl ) -methylamino] -benzyl} -piperazin-1-yl) -2-oxoethyl] acrylamide 0.77 800,21 57 (S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- [1-benzyl-2- (4- {4 - [(2-hydroxyethyl) methylamino] benzyl} - piperazin-1-yl) -2-oxoethyl] -3- (4-propoxyphenyl) acrylamide 0.92 801.22

Compound of Example No. Chemical name LC-MS * Rt (min) [M + H] ⁺ 58 (S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- [1-benzyl-2- (4- {4 - [(2-hydroxyethyl) methylamino] benzyl} - piperazin-1-yl) -2-oxoethyl] -3- (4-isopropoxyphenyl) acrylamide 0.91 801.25 59 (S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- [1-benzyl-2- (4- {4 - [(2-hydroxyethyl) methylamino] benzyl} - piperazin-1-yl) -2-oxoethyl] -3- (4-ethylphenyl) acrylamide 0.92 771.29 60 (S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- [1-benzyl-2- (4- {4 - [(2-hydroxyethyl) methylamino] benzyl} - piperazin-1-yl) -2-oxoethyl] -3- (4-difluoromethoxyphenyl) acrylamide 0.87 808.87 61 (S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- [1-benzyl-2- (4- {4 - [(2-hydroxyethyl) methylamino] benzyl} - piperazin-1-yl) -2-oxoethyl] -3- (4-isopropylphenyl) acrylamide 0.94 787.34 62 (S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- [1-benzyl-2- (4- {4 - [(2-hydroxyethyl) methylamino] benzyl} - piperazin-1-yl) -2-oxoethyl] -3- (4-tert-butylphenyl) acrylamide 0.97 799.22 * analytical HPLC I, column X-Bridge, alkaline medium.

Obtaining compounds of formula I by the synthesis pathway shown in Scheme 3 - general methods and examples:

Step 1: (S) -2- [4- (4-acetylpiperazin-1-yl) benzylamino] -3-phenylpropionic acid methyl ester.

Secondary amine 18 is prepared according to general C1 or C2 procedures and is used in the next step without further purification. Rt = 0.82; [M + H] ⁺ = 396.20 (analytical HPLC I, X-Bridge column, alkaline medium).

Stage 2

Compounds of formula 20 are prepared according to general procedures D1 or D2.

Intermediate No. Chemical name Exit LC-MS Rt (min) [M + H] ⁺ Conditions 17 (S) -2 - {[4- (4-acetylpiperazin-1-yl) benzyl] - [3- (4-trifluoromethylphenyl) acryloyl] amino} -3-phenylpropionic acid methyl ester 70% 0.96 594.15 analytical HPLC I, X-Bridge column, alkaline medium

General Procedure G - Stage 3

To a solution of 1 mmol of methyl ester 20 in 8 ml of Et ₂ O and 2 ml of H ₂ O at 0 ° C, 10 mmol of a 2M aqueous NaOH solution was added dropwise. The reaction mixture was further stirred at RT for 2-3 hours. After stirring, the aqueous phase was acidified with 1N HC1 solution to pH = 2-3 and then extracted with EtOAc (x3). The combined organic phases are washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue is used in the next step without further purification.

Intermediate No. Chemical name Exit LC-MS Rt (min) [M + H] ⁺ Conditions eighteen (S) -2 - {[4- (4-Acetylpiperazin-1-yl) benzyl] - [3- (4-trifluoromethylphenyl) acryloyl] amino} -3-phenylpropionic acid 78% 0.97 580.12 analytical HPLC I, X-Bridge column, alkaline medium

Stage 4

Compounds of Formula 8 are prepared according to General Procedure A. The residue is purified by flash chromatography (SiO ₂ 60F) or preparative HPLC to give the final compound.

Compound of Example No. Chemical name LC-MS * Rt (min) [M + H] ⁺ 63 (S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- {1-benzyl-2- [4- (4-methoxybenzyl) piperazin-1-yl] -2-oxoethyl } -3- (4-trifluoromethylphenyl) acrylamide 0.99 768.24

Compound of Example No. Chemical name LC-MS * Rt (min) [M + H] ⁺ 64 (S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- {1-benzyl-2- [4- (4-nitrobenzyl) piperazin-1-yl] -2-oxoethyl } -3- (4-trifluoromethylphenyl) acrylamide 0.99 783.22 65 (S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- {1-benzyl-2- [4- (4-isopropoxybenzyl) piperazin-1-yl] -2-oxoethyl } -3- (4-trifluoromethylphenyl) acrylamide 1,02 796.24 * analytical HPLC I, column X-Bridge, alkaline medium.

The compounds of Examples 66-73 were prepared according to General Procedure D2.

Compound of Example No. Chemical name LC-MS * Rt (min) [M + H] ⁺ 66 (S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- {1- (4- (4- (dimethylamino) benzyl) piperazin-1-yl) -1-oxo-3- phenylpropan-2-yl} cinnamide 0.94 713.13 67 (S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -] - N- {1- [4- (4- (dimethylamino) benzyl) piperazin-1-yl] -1-oxo- 3-phenylpropan-2-yl} -3- (p-tolyl) acrylamide 0.97 727.45 68 (S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- {1- (4- (4- (dimethylamino) benzyl) piperazin-1-yl) -1-oxo-3- phenylpropan-2-yl} -3- (4-propylphenyl) acrylamide 1,04 755.45 69 (S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- {1- (4- (4- (dimethylamino) benzyl) piperazin-1-yl) -1-oxo-3- phenylpropan-2-yl} -3- (4-methoxyphenyl) acrylamide 0.93 743.46 70 (S) -3- (4-Acetylphenyl) -N- [4- (4-acetylpiperazin-1-yl) benzyl] -N- {1- (4- (4- (dimethylamino) benzyl) piperazin-1-yl ) -1-oxo-3-phenylpropan-2-yl} acrylamide 0.91 755.43 71 (S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -3- (4-cyanophenyl) -N- {1- (4- (4- (dimethylamino) benzyl) piperazin-1-yl ) -1-oxo-3-phenylpropan-2-yl} acrylamide 0.92 738.44

Compound of Example No. Chemical name LC-MS * Rt (min) [M + H] ⁺ 72 (S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- {1- (4- (4- (dimethylamino) benzyl) piperazin-1-yl) -1-oxo-3- phenylpropan-2-yl} -3- (4-fluorophenyl) acrylamide 0.95 731.42 73 (S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -3- (4-chlorophenyl) -N- {1- (4- (4- (dimethylamino) benzyl) piperazin-1-yl ) -1-oxo-3-phenylpropan-2-yl} acrylamide 0.98 747.28 * analytical HPLC I, column X-Bridge, alkaline medium.

In vitro anti-malarial activity: Plasmodium falciparum m vitro study

T vitro activity against P. falciparum, which is in the erythrocyte stages, in human erythrocytes is determined by the study of [ ³ H] -poxanthine incorporation. In this study, one strain is used that is sensitive to all known drugs (P. Falciparum NF54), and the activity of all test compounds is compared with the activity of standard drugs, chlorchine (Sigma C6628) and artesunate (Sigma 36, 159-3). In 96-well microtiter plates, the compounds tested twice are serially diluted in a screening medium [RPMI 1640 medium supplemented with HEPES (N-2-hydroxyethylpiperazine-N-2-ethanesulfonic acid) (5.94 g / l), NaHCO ₃ (2.1 g / l), neomycin (100 U / ml) and Albumax (5 g / l) or human serum (final concentration 50%)] in the appropriate concentration range. Then, parasitic cultures are incubated in a screening medium containing washed human red blood cells characterized by a hematocrit of 2.5% (parasitemia 0.3%) and added to serially diluted compounds and incubated in a humidified atmosphere at 37 ° C, 4% CO ₂ , 3% 02 and 93% N ₂ . After 48 hours, [ ³ H-hypoxanthine (0.5 μCi) was added to each well of the plate. The plates were incubated under the same conditions for another 24 hours, then the cells were harvested using a Betaplate cell harvester (Wallac) and washed with distilled water. The dried filters are inserted into a plastic foil containing 10 ml of scintillation liquid, and a count is made using a Betaplate liquid scintillation counter. IC ₅₀ values are calculated from the sigmoidal inhibition curves using Microsoft Excel.

Table 1 IC ₅₀ Values (nM) for Compounds of Formula I Compound of Example No. IC ₅₀ with respect to NF54 (with Albumax) IC ₅₀ in relation to NF54 (with 50% serum) 1 (comparative example) 5.1 27.6 2 2.0 10 3 1.9 8.5 four 1.9 10 5 3.9 12 6 9,4 32 7 3,1 40 8 1.8 13,4 9 2,4 7.3 10 3.0 8.6 eleven 4.0 21 12 17 74 13 12 46 fourteen 3,7 twenty fifteen 1.7 6.8 16 5.5 13.3 17 4.3 39 eighteen 2,5 11.8 19 2.6 9.3 twenty 1,2 7.1 21 1.9 7 22 1.3 10.9 23 1.3 9.5 24 2,8 13.9 25 1,2 4.7 26 eighteen 33 27 1.8 12.9 28 1,1 3.6 29th 1,1 3,7 thirty 0.9 5,0 31 1.7 3.8 32 0.5 4.4 33 3.3 10.9 34 0.5 3.8 35 2.9 9 36 7.8 28 37 3.2 28 38 1.8 9 39 2,3 eleven 40 1.7 10.5 41 2.9 12.5 42 1.7 13.7 43 1,1 13.5 44 0.4 2,8 45 0.2 1.8 46 0.4 1,1 47 0.5 3,5 48 0.5 1,6 49 0.8 3,1 fifty 1,6 9.3 51 10.7 29.8 52 10 33 53 4.3 12,4 54 1,6 5.9 55 7.5 14.8 57 1.7 5.1 58 1.4 3.9 59 1,6 3.8 60 3 8.1 61 1,2 6.7 62 0.7 3.2 63 3.2 17.8 64 3,5 43 65 2,8 fourteen 66 24.6 113 67 <3.1 17.5 68 0.7 8 69 <3.1 17 70 <3.1 16 71 eighteen 62 72 10 91 73 3.3 26 Chlorhin 4.2 3.8 Artesunate 2.7 one

In vivo antimalarial efficacy studies In vivo antimalarial activity is determined for groups of 3 female NMRI mice (20-22 g), which are infected with P. berghei GFP-ANKA strain (0.2 ml of heparinized saline solution on day 0) containing 2 × 10 ⁷ parasite-infected red blood cells). In control mice, parasitemia usually reaches about 40% on day 3 after infection. Compounds are prepared in a Tween 80 / ethanol (7% / 3%) mixture, usually at concentrations of 10 mg / ml. Compounds are administered at a volume of 10 ml / kg orally in single doses (1 × 100 mg / kg, 24 hours after infection). 48 hours after drug administration (on day 3 after infection), 1 μl of blood was taken from the tail, resuspended in 1 ml of PBS and parasitemia was determined using a FACScan (Becton Dickinson) apparatus by counting 100,000 red blood cells. Activity is calculated as the difference between the average values for the control group and for the experimental groups and it is expressed as a percentage of the value for the control group.

table 2 The activity (inhibition of parasitemia) of the compounds of formula I after oral administration of a single dose of 100 mg / kg, expressed as a percentage of the value for the control group Compound of Example No. Activity [%] Compound of Example No. Activity [%] one* <40 34 99,2 2 94.1 35 98.7 3 98.7 36 46.8 four 97.4 38 98.5 5 <40 39 99 6 80,4 40 93.6 7 44.7 41 71 8 99,4 42 97.3 9 99.1 43 98.7 10 96 44 99.0 fifteen 99 45 99,4 16 85.9 46 98.9 eighteen 99.1 47 98.4 19 99,2 48 99 twenty 98.5 49 98.6 21 98.8 fifty 98 22 99.3 52 <40 23 99.1 53 52.3 24 79.2 54 93.7 25 99.1 55 <40 27 <40 57 98.2 28 99.3 58 98.2 29th 99,2 59 96.5 thirty 97.7 60 78.3 31 88.9 61 98.8 32 98.5 62 99,4 33 97.4 * comparative example

Claims (22)

1. The compound of formula I:

wherein
- X is CH or N;
R ¹ is —NO ₂ , —N (CH ₃ ) ₂ or —NCH ₃ (CH ₂ CH ₂ OH); and
R ² is hydrogen, methyl, ethyl, n-propyl, isopropyl, tert-butyl, cyano, halogen, methoxy, ethoxy, n-propoxy, isopropoxy, trifluoromethyl, difluoromethoxy, methylsulfonyl, acetyl or acetylamino; or
- X is CH, R ¹ is hydrogen and R ² is ethyl, isopropyl, tert-butyl, ethoxy, n-propoxy, isopropoxy, methylsulfonyl, acetylamino or methoxycarbonyl; or
- X is CH, R ¹ is cyano and R ² is ethyl, isopropyl, tert-butyl, ethoxy, n-propoxy, isopropoxy, trifluoromethyl, difluoromethoxy, trifluoromethoxy, methylsulfonyl or acetylamino; or
- X is CH, R ¹ is chloro and R ² is ethyl, isopropyl, tert-butyl, ethoxy, n-propoxy, isopropoxy, difluoromethoxy, methylsulfonyl or acetylamino; or
- X is CH, R ¹ is a methoxy group or an isopropoxy group, and R ² is trifluoromethyl; or
- X is CH, R ¹ is methylsulfonyl or ethylsulfonyl and R ² is trifluoromethyl, ethyl, isopropyl, tert-butyl, ethoxy, n-propoxy, isopropoxy or difluoromethoxy;
or a pharmaceutically acceptable salt of such a compound. 2. The compound according to claim 1, in which
- X is CH or N;
R ¹ is —NO ₂ , —N (CH ₃ ) ₂ or —NCH ₃ (CH ₂ CH ₂ OH); and
R ² is hydrogen, methyl, ethyl, n-propyl, isopropyl, tert-butyl, cyano, halogen, methoxy, ethoxy, n-propoxy, isopropoxy, trifluoromethyl, difluoromethoxy, methylsulfonyl, acetyl or acetylamino; or
- X is CH, R ¹ is hydrogen and R ² is ethyl, isopropyl, tert-butyl, ethoxy, n-propoxy, isopropoxy, methylsulfonyl, acetylamino or methoxycarbonyl; or
- X is CH, R ¹ is cyano and R ² is ethyl, isopropyl, tert-butyl, ethoxy, n-propoxy, isopropoxy, trifluoromethyl, difluoromethoxy, trifluoromethoxy, methylsulfonyl or acetylamino; or
- X is CH, R ¹ is chloro and R ² is ethyl, isopropyl, tert-butyl, ethoxy, n-propoxy, isopropoxy, difluoromethoxy, methylsulfonyl or acetylamino; or
- X is CH, R ¹ is a methoxy group or an isopropoxy group, and R ² is trifluoromethyl;
or a pharmaceutically acceptable salt of such a compound. 3. The compound according to claim 1, in which
- X is CH or N;
R ¹ is —NO ₂ , —N (CH ₃ ) ₂ or —NCH ₃ (CH ₂ CH ₂ OH); and
R ² is ethyl, isopropyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, trifluoromethyl, difluoromethoxy, methylsulfonyl or acetylamino; or
- X is CH, R ¹ is hydrogen and R ² is ethyl, isopropyl, tert-butyl, ethoxy, n-propoxy, isopropoxy, methylsulfonyl, acetylamino or methoxycarbonyl; or
- X is CH, R ¹ is cyano and R ² is ethyl, isopropyl, tert-butyl, ethoxy, n-propoxy, isopropoxy, trifluoromethyl, difluoromethoxy, trifluoromethoxy, methylsulfonyl or acetylamino; or
- X is CH, R ¹ is chloro and R ² is ethyl, isopropyl, tert-butyl, ethoxy, n-propoxy, isopropoxy, difluoromethoxy, methylsulfonyl or acetylamino; or
- X is CH, R ¹ is a methoxy group or an isopropoxy group, and R ² is trifluoromethyl;
or a pharmaceutically acceptable salt of such a compound. 4. The compound according to claim 1, in which
R ¹ is —NO ₂ , —N (CH ₃ ) ₂ or —NCH ₃ (CH ₂ CH ₂ OH); and R ² is hydrogen, methyl, ethyl, n-propyl, isopropyl, tert-butyl, cyano, halogen, methoxy, ethoxy, n-propoxy, isopropoxy, trifluoromethyl, difluoromethoxy, methylsulfonyl, acetyl or acetylamino;
or a pharmaceutically acceptable salt of such a compound. 5. The compound according to claim 1, in which
R ¹ is —NO ₂ , —N (CH ₃ ) ₂ or —NCH ₃ (CH ₂ CH ₂ OH); and
R ² is ethyl, isopropyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, trifluoromethyl, difluoromethoxy, methylsulfonyl or acetylamino;
or a pharmaceutically acceptable salt of such a compound. 6. The compound of claim 4 or 5, wherein X is CH, or a pharmaceutically acceptable salt of such a compound. 7. The compound of claim 4 or 5, wherein X is N, or a pharmaceutically acceptable salt of such a compound. 8. The compound of claim 4 or 5, wherein R ¹ is —NO ₂ , or a pharmaceutically acceptable salt of such a compound. 9. The compound of claim 4 or 5, wherein R ¹ is —N (CH ₃ ) ₂ , or a pharmaceutically acceptable salt of such a compound. 10. The compound of claim 4 or 5, wherein R ¹ is —NCH ₃ (CH ₂ CH ₂ OH), or a pharmaceutically acceptable salt of such a compound. 11. The compound of claim 4 or 5, wherein R ² is ethyl, isopropyl, tert-butyl, ethoxy, n-propoxy or isopropoxy, or a pharmaceutically acceptable salt of such a compound. 12. The compound of claim 11, wherein R ² is an isopropoxy group, or a pharmaceutically acceptable salt of such a compound. 13. The compound of claim 4 or 5, wherein R ² is trifluoromethyl, difluoromethoxy, methylsulfonyl or acetylamino, or a pharmaceutically acceptable salt of such a compound. 14. The compound of claim 4 or 5, wherein R ² is a methoxy group, or a pharmaceutically acceptable salt of such a compound. 15. The compound of claim 4, wherein R ² is hydrogen, methyl, n-propyl, cyano, halogen or acetyl, or a pharmaceutically acceptable salt of such a compound. 16. The compound according to claim 1, selected from the group including:
(S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- {1-benzyl-2- [4- (4-dimethylaminobenzyl) piperazin-1-yl] -2-oxoethyl } -3- (4-trifluoromethylphenyl) acrylamide,
(S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- {1-benzyl-2- [4- (4-dimethylaminobenzyl) piperazin-1-yl] -2-oxoethyl } -3- (6-trifluoromethylpyridin-3-yl) -acrylamide,
(S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- {1-benzyl-2- [4- (4-dimethylaminobenzyl) piperazin-1-yl] -2-oxoethyl } -3- (6-methoxypyridin-3-yl) acrylamide,
(S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- {1-benzyl-2- [4- (4-dimethylaminobenzyl) piperazin-1-yl] -2-oxoethyl } -3- (6-ethoxypyridin-3-yl) acrylamide,
(S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- {1-benzyl-2- [4- (4-dimethylaminobenzyl) piperazin-1-yl] -2-oxoethyl } -3- (4-ethoxyphenyl) acrylamide,
(S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- {1-benzyl-2- [4- (4-dimethylaminobenzyl) piperazin-1-yl] -2-oxoethyl } -3- (4-methanesulfonylphenyl) acrylamide,
(S) -3- (4-Acetylaminophenyl) -N- [4- (4-acetylpiperazin-1-yl) benzyl] -N- {1-benzyl-2- [4- (4-dimethylaminobenzyl) piperazine- 1-yl] -2-oxoethyl} acrylamide,
(S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- {1-benzyl-2- [4- (4-dimethylaminobenzyl) piperazin-1-yl] -2-oxoethyl } -3- (4-propoxyphenyl) acrylamide,
(S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- {1-benzyl-2- [4- (4-dimethylaminobenzyl) piperazin-1-yl] -2-oxoethyl } -3- (4-isopropoxyphenyl) acrylamide,
(S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- {1-benzyl-2- [4- (4-dimethylaminobenzyl) piperazin-1-yl] -2-oxoethyl } -3- (4-ethylphenyl) acrylamide,
(S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- {1-benzyl-2- [4- (4-dimethylaminobenzyl) piperazin-1-yl] -2-oxoethyl } -3- (4-difluoromethoxyphenyl) acrylamide,
(S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- {1-benzyl-2- [4- (4-dimethylaminobenzyl) piperazin-1-yl] -2-oxoethyl } -3- (4-tert-butylphenyl) acrylamide,
(S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- {1-benzyl-2- [4- (4-dimethylaminobenzyl) piperazin-1-yl] -2-oxoethyl } -3- (4-isopropylphenyl) acrylamide,
(S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- [1-benzyl-2- (4- {4 - [(2-hydroxyethyl) methylamino] benzyl} - piperazin-1-yl) -2-oxoethyl] -3- (4-trifluoromethylphenyl) acrylamide,
(S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- [1-benzyl-2- (4- {4 - [(2-hydroxyethyl) methylamino] benzyl} - piperazin-1-yl) -2-oxoethyl] -3- (6-trifluoromethylpyridin-3-yl) acrylamide,
(S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- [1-benzyl-2- (4- {4 - [(2-hydroxyethyl) methylamino] benzyl} - piperazin-1-yl) -2-oxoethyl] -3- (6-methoxypyridin-3-yl) acrylamide,
(S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- [1-benzyl-2- (4- {4 - [(2-hydroxyethyl) methylamino] benzyl} - piperazin-1-yl) -2-oxoethyl] -3- (6-ethoxypyridin-3-yl) acrylamide,
(S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- [1-benzyl-2- (4- {4 - [(2-hydroxyethyl) methylamino] benzyl} - piperazin-1-yl) -2-oxoethyl] -3- (4-ethoxyphenyl) acrylamide,
(S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- [1-benzyl-2- (4- {4 - [(2-hydroxyethyl) methylamino] benzyl} - piperazin-1-yl) -2-oxoethyl] -3- (4-methanesulfonylphenyl) acrylamide,
(S) -3- (4-Acetylaminophenyl) -N- [4- (4-acetylpiperazin-1-yl) benzyl] -N- [1-benzyl-2- (4- {4 - [(2-hydroxyethyl ) -methylamino] -benzyl} -piperazin-1-yl) -2-oxoethyl] acrylamide,
(S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- [1-benzyl-2- (4- {4 - [(2-hydroxyethyl) methylamino] benzyl} - piperazin-1-yl) -2-oxoethyl] -3- (4-propoxyphenyl) acrylamide,
(S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- [1-benzyl-2- (4- {4 - [(2-hydroxyethyl) methylamino] benzyl} - piperazin-1-yl) -2-oxoethyl] -3- (4-isopropoxyphenyl) acrylamide,
(S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- [1-benzyl-2- (4- {4 - [(2-hydroxyethyl) methylamino] benzyl} - piperazin-1-yl) -2-oxoethyl] -3- (4-ethylphenyl) acrylamide,
(S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- [1-benzyl-2- (4- {4 - [(2-hydroxyethyl) methylamino] benzyl} - piperazin-1-yl) -2-oxoethyl] -3- (4-difluoromethoxyphenyl) acrylamide,
(S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- [1-benzyl-2- (4- {4 - [(2-hydroxyethyl) methylamino] benzyl} - piperazin-1-yl) -2-oxoethyl] -3- (4-isopropylphenyl) acrylamide,
(S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- [1-benzyl-2- (4- {4 - [(2-hydroxyethyl) methylamino] benzyl} - piperazin-1-yl) -2-oxoethyl] -3- (4-tert-butylphenyl) acrylamide, and
(S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- {1-benzyl-2- [4- (4-nitrobenzyl) piperazin-1-yl] -2-oxoethyl } -3- (4-trifluoromethylphenyl) acrylamide,
or pharmaceutically acceptable salts of these compounds. 17. The compound according to claim 1, selected from the group including:
(S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- {1- (4- (4- (dimethylamino) benzyl) piperazin-1-yl) -1-oxo-3- phenylpropan-2-yl} cinnamide,
(S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- {1- [4- (4- (dimethylamino) benzyl) piperazin-1-yl] -1-oxo-3- phenylpropan-2-yl} -3- (p-tolyl) acrylamide,
(S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- {1- (4- (4- (dimethylamino) benzyl) piperazin-1-yl) -1-oxo-3- phenylpropan-2-yl} -3- (4-propylphenyl) acrylamide,
(S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- {1- (4- (4- (dimethylamino) benzyl) piperazin-1-yl) -1-oxo-3- phenylpropan-2-yl} -3- (4-methoxyphenyl) acrylamide,
(S) -3- (4-Acetylphenyl) -N- [4- (4-acetylpiperazin-1-yl) benzyl] -N- {1- (4- (4- (dimethylamino) benzyl) piperazin-1-yl ) -1-oxo-3-phenylpropan-2-yl} acrylamide,
(S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -3- (4-cyanophenyl) -N- {1- (4- (4- (dimethylamino) benzyl) piperazin-1-yl ) -1-oxo-3-phenylpropan-2-yl} acrylamide,
(S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- {1- (4- (4- (dimethylamino) benzyl) piperazin-1-yl) -1-oxo-3- phenylpropan-2-yl} -3- (4-fluorophenyl) acrylamide, and
(S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -3- (4-chlorophenyl) -N- {1- (4- (4- (dimethylamino) benzyl) piperazin-1-yl ) -1-oxo-3-phenylpropan-2-yl} acrylamide,
or pharmaceutically acceptable salts of these compounds. 18. The compound according to claim 1, selected from the group including:
(S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- [1-benzyl-2- (4-benzylpiperazin-1-yl) -2-oxoethyl] -3- (4 ethyl phenyl) acrylamide,
(S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- [1-benzyl-2- (4-benzylpiperazin-1-yl) -2-oxoethyl] -3- (4 tert-butylphenyl) acrylamide,
(S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- [1-benzyl-2- (4-benzylpiperazin-1-yl) -2-oxoethyl] -3- (4 ethoxyphenyl) acrylamide,
(S) -4- (2 - {[4- (4-acetylpiperazin-1-yl) benzyl] - [1-benzyl-2- (4-benzylpiperazin-1-yl) -2-oxoethyl] methyl ester - carbamoyl} -vinyl) -benzoic acid,
(S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- [1-benzyl-2- (4-benzylpiperazin-1-yl) -2-oxoethyl] -3- (4 methanesulfonylphenyl) acrylamide,
(S) -3- (4-Acetylaminophenyl) -N- [4- (4-acetylpiperazin-1-yl) benzyl] -N- [1-benzyl-2- (4-benzylpiperazin-1-yl) -2 -oxoethyl] -acrylamide,
(S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- [1-benzyl-2- (4-benzylpiperazin-1-yl) -2-oxoethyl] -3- (4 propoxyphenyl) acrylamide,
(S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- [1-benzyl-2- (4-benzylpiperazin-1-yl) -2-oxoethyl] -3- (4 isopropoxyphenyl) acrylamide,
(S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- [1-benzyl-2- (4-benzylpiperazin-1-yl) -2-oxoethyl] -3- (4 isopropylphenyl) acrylamide,
(S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- {1-benzyl-2- [4- (4-cyanobenzyl) piperazin-1-yl] -2-oxoethyl } -3- (4-trifluoromethylphenyl) acrylamide,
(S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- {1-benzyl-2- [4- (4-cyanobenzyl) piperazin-1-yl] -2-oxoethyl } -3- (4-ethoxyphenyl) acrylamide,
(S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- {1-benzyl-2- [4- (4-cyanobenzyl) piperazin-1-yl] -2-oxoethyl } -3- (4-methanesulfonylphenyl) acrylamide,
(S) -3- (4-Acetylaminophenyl) -N- [4- (4-acetylpiperazin-1-yl) benzyl] -N- {1-benzyl-2- [4- (4-cyanobenzyl) piperazine- 1-yl] -2-oxoethyl} acrylamide,
(S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- {1-benzyl-2- [4- (4-cyanobenzyl) piperazin-1-yl] -2-oxoethyl } -3- (4-propoxyphenyl) acrylamide,
(S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- {1-benzyl-2- [4- (4-cyanobenzyl) piperazin-1-yl] -2-oxoethyl } -3- (4-isopropoxyphenyl) acrylamide,
(S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- {1-benzyl-2- [4- (4-cyanobenzyl) piperazin-1-yl] -2-oxoethyl } -3- (4-ethylphenyl) acrylamide,
(S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- {1-benzyl-2- [4- (4-cyanobenzyl) piperazin-1-yl] -2-oxoethyl } -3- (4-difluoromethoxyphenyl) acrylamide,
(S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- {1-benzyl-2- [4- (4-cyanobenzyl) piperazin-1-yl] -2-oxoethyl } -3- (4-isopropylphenyl) acrylamide,
(S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- {1-benzyl-2- [4- (4-cyanobenzyl) piperazin-1-yl] -2-oxoethyl } -3- (4-trifluoromethoxyphenyl) acrylamide,
(S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- {1-benzyl-2- [4- (4-cyanobenzyl) piperazin-1-yl] -2-oxoethyl } -3- (4-tert-butylphenyl) acrylamide,
(S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- {1-benzyl-2- [4- (4-chlorobenzyl) piperazin-1-yl] -2-oxoethyl } -3- (4-ethoxyphenyl) acrylamide,
(S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- {1-benzyl-2- [4- (4-chlorobenzyl) piperazin-1-yl] -2-oxoethyl } -3- (4-methanesulfonylphenyl) acrylamide,
(S) -3- (4-Acetylaminophenyl) -N- [4- (4-acetylpiperazin-1-yl) benzyl] -N- {1-benzyl-2- [4- (4-chlorobenzyl) piperazine- 1-yl] -2-oxoethyl} acrylamide,
(S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- {1-benzyl-2- [4- (4-chlorobenzyl) piperazin-1-yl] -2-oxoethyl } -3- (4-propoxyphenyl) acrylamide,
(S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- {1-benzyl-2- [4- (4-chlorobenzyl) piperazin-1-yl] -2-oxoethyl } -3- (4-isopropoxyphenyl) acrylamide,
(S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- {1-benzyl-2- [4- (4-chlorobenzyl) piperazin-1-yl] -2-oxoethyl } -3- (4-ethylphenyl) acrylamide,
(S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- {1-benzyl-2- [4- (4-chlorobenzyl) piperazin-1-yl] -2-oxoethyl } -3- (4-difluoromethoxyphenyl) acrylamide,
(S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- {1-benzyl-2- [4- (4-chlorobenzyl) piperazin-1-yl] -2-oxoethyl } -3- (4-isopropylphenyl) acrylamide,
(S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- {1-benzyl-2- [4- (4-chlorobenzyl) piperazin-1-yl] -2-oxoethyl } -3- (4-tert-butylphenyl) acrylamide,
(S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- {1-benzyl-2- [4- (4-methoxybenzyl) piperazin-1-yl] -2-oxoethyl } -3- (4-trifluoromethylphenyl) acrylamide, and
(S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- {1-benzyl-2- [4- (4-isopropoxybenzyl) piperazin-1-yl] -2-oxoethyl } -3- (4-trifluoromethylphenyl) acrylamide,
or pharmaceutically acceptable salts of these compounds. 19. The compound according to claim 1, selected from the group including:
(S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- {1-benzyl-2- [4- (4- (methylsulfonyl) benzyl) piperazin-1-yl] -2-oxoethyl} -3- (4-isopropoxyphenyl) acrylamide,
(S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- {1-benzyl-2- [4- (4- (methylsulfonyl) benzyl) piperazin-1-yl] -2-oxoethyl} -3- (4-tert-butylphenyl) acrylamide,
(S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- {1-benzyl-2- [4- (4- (methylsulfonyl) benzyl) piperazin-1-yl] -2-oxoethyl} -3- (4-propoxyphenyl) acrylamide,
(S) -N- (4- (4-Acetylpiperazin-1-yl) benzyl) -N- (1- (4- (4- (methylsulfonyl) benzyl) piperazin-1-yl) -1-oxo-3- phenylpropan-2-yl) -3- (4- (trifluoromethyl) phenyl) acrylamide,
(S) -N- [4- (4-Acetylpiperazin-1-yl) benzyl] -N- {1-benzyl-2- [4- (4- (ethylsulfonyl) benzyl) piperazin-1-yl] -2-oxoethyl} -3- (4-propoxyphenyl) acrylamide, and
(S) -N- (4- (4-Acetylpiperazin-l-yl) benzyl) -N- (1- (4- (4- (ethylsulfonyl) benzyl) piperazin-1-yl) -1-oxo-3- phenylpropan-2-yl) -3- (4- (trifluoromethyl) phenyl) acrylamide,
or pharmaceutically acceptable salts of these compounds. 20. A pharmaceutical composition for treating and / or preventing malaria caused by Plasmodium falciparum, containing in a pharmaceutically active amount a compound according to any one of claims. 1-19 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. 21. The compound according to any one of paragraphs. 1-5, 12, 15 and 16-19 or a pharmaceutically acceptable salt thereof as a medicament for the treatment and / or prevention of malaria caused by Plasmodium falciparum. 22. The use of compounds according to any one of paragraphs. 1-19 or a pharmaceutically acceptable salt thereof for the preparation of a pharmaceutical composition for the treatment and / or prevention of malaria caused by Plasmodium falciparum.